Association between circulating biomarkers of one-carbon metabolism and glymphatic system function in cognitive decline of Alzheimer’s disease

Introduction Dysfunction in both one-carbon metabolism (OCM) and the glymphatic system has been implicated in the pathogenesis of Alzheimer’s disease (AD). However, the potential interrelationship remains poorly understood. This study aimed to investigate the association between OCM biomarkers and glymphatic function in AD and explore their combined effects on cognition. Methods A total of 210 participants were enrolled, including 68 with normal cognition (NC), 75 with mild cognitive impairment due to AD (AD-MCI), and 67 with dementia due to AD (AD-D). Circulating OCM biomarkers were measured, including serum folate, vitamin B12, and homocysteine levels. Glymphatic-related function was evaluated using the diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) index, and comprehensive neuropsychological assessments were performed. Results Serum folate levels ( p = 0.020) and DTI-ALPS index ( p 0.001) differed significantly between NC and AD groups, with more pronounced differences among female ( p = 0.005; 0.001) and late-life ( p = 0.046; 0.021) subgroups. In AD patients, folate levels were positively correlated with DTI-ALPS index ( r = 0.212, p FDR = 0.032), and both were associated with domain-specific cognitive performance. The low-risk group (high folate and high DTI-ALPS index) outperformed the high-risk group in memory ( p = 0.001) and processing speed ( p = 0.005), and showed higher MMSE ( p = 0.021) and memory scores ( p = 0.003) than the moderate-risk group. Conclusion Lower serum folate levels and reduced DTI-ALPS index were associated with poorer cognitive performance in AD. Their co-occurrence was linked to worse cognitive outcomes. These findings suggest a potential association between metabolic status and glymphatic function in AD, which requires confirmation in longitudinal studies.